Multiple sclerosis (MS) is an inflammatory attack on the central nervous system (CNS) that results in extensive demyelination and loss of neuronal function that often leads to death. Experimental autoimmune encephalomyelitis (EAE) is the animal model for MS. This proposal will examine the regulation of the immune system response by epicutaneous (skin) immunization with self-antigen. Epicutaneous immunization is a process whereby, a skin patch soaked in antigen, in this case the CNS antigen myelin oligodendrocyte gylcpprotein (MOG), is applied to the shaved skin of mice prior to inducing EAE with the same antigen. We have recently shown that when we carry out epicutaneous immunization or skin patching with MOG in C57BL/6 mice prior to EAE induction that these mice are protected from developing EAE. Most importantly, when we apply epicutaneous immunization to mice after they develop EAE, mice with mild EAE are protected, but not mice with severe EAE. We observed that the CD4 T cells from mice that are protected from EAE produced high levels of IL-10 and they can transfer protection to na[unreadable]ve recipient mice. We also found that the epidermal dendritic cells in the skin that captured antigen from the patch can suppress EAE when they are isolated from the skin after epicutaneous immunization and transferred into na[unreadable]ve recipient mice. The goal of this proposal is set out in three specific aims that will determine 1) whether epicutaneous immunization/skin patching with MOG can ameliorate ongoing EAE in mice and reduce or prevent relapses; 2) determine whether tolerance mediated by CD4 T cells in mice epicutaneously immunized with MOG is dependent on IL-10 and 3) determine the role of epidermal dendritic cells in epicutaneous immunization-induced tolerance. These studies will serve to advance our knowledge of autoimmune disease regulation both at the peripheral level and at the CNS level and could be beneficial to MS and other autoimmune diseases.